TOTAL SYNTHESIS OF (+/-)-VALLESAMIDINE

This article reports full details of a project aimed at providing synthetic access to the 2,2,3-trialkylindoline alkaloids such as vallesamidine (4). The basic strategy was to preassemble the tricyclic portion containing the nonindolic nitrogen and to form the indoline ring at a late stage in the synthesis. An approach summarized in the retrosynthetic analysis summarized in Scheme III failed because enones 48 and 50 do not undergo 1,4-addition of nitrogen nucleophiles. However, the retrosynthesis summarized in Scheme X did lead to a successful synthesis of (±)-4. The synthesis requires seven steps from 2-ethylcyclopentanone [→54 56 →66 →68 →71 →74 (±)-4] and delivers the alkaloid in 19% overall yield. Pivotal steps in the synthesis are the lactam annelation process in which 56 reacts with o-nitrocinnamic acid to yield 66 and the NBS-mediated cyclization of amino lactam 68 to the pentacyclic bromo lactam 70. Four of the seven steps involve the formation of skeletal (C—C or C—N) bonds and only three are functional-group transformations. © 1990, American Chemical Society. All rights reserved.